1. Field of the Invention
The present invention relates to an improved method or process for treating and healing a bone void, and in particular to a method for efficiently incorporating a biologically active agent into the interstices (voids or pores) of a porous hydrophobic biodegradable material wherein the biologically active agent is deposited upon the internal surfaces defining the voids or pores of the biodegradable material.
2. Statement of Related Art
Bone wounds, as well as many other wound models, initiate a release of biologically active agents critical to the wound healing process. Bone morphogenic proteins (BMP), which naturally occur in bone, once released from the wound, stimulate osteoinduction and regenerate lost or damaged bone tissue. These same proteins, in a purified form, can be used to stimulate bone growth into a biodegradable matrix allowing for artificial creation of bone both within and external to the normal skeletal boundaries.
In recent years much work has been done in developing biodegradable porous delivery vehicles for the controlled release of substances while also providing a location for cellular attachment and guided tissue regeneration. Present biodegradable materials can be separated into two categories: 1) those which are hydrophilic; and 2) those which are hydrophobic. Hydrophilic materials (demineralized freeze dried bone, ceramic, fibrin, gelatin, etc.) possess a high affinity for water which provides for easy incorporation of the aqueous protein solutions within the internal porosity of the material, however, most are limited in their overall range of porosity, gross size, shape and mechanical characteristics. Hydrophobic materials (L-polylactic acid, D,L-polylactic acid, poly-glycolic acid, etc.), which possess little or no affinity for water, are potentially limitless in their range of porosities, gross size, shape and mechanical characteristics, but only permit easy deposition of aqueous solutions upon the external surfaces. Limited, incomplete deposition of the solution occurs within the internal porosities. This incomplete coating of the internal surfaces creates dead spaces which hinder and even prevent cellular integration. Hydrophobic materials may be impregnated with the protein creating a much more uniform distribution, but this results in a torpid release of the proteins as the polymer degrades making a large percentage of it unavailable for the critical window of time during which the protein is needed to activate regenerative processes. Thus, special procedures are required to efficiently incorporate aqueous protein solutions throughout internal porosities of hydrophobic biodegradable materials.
U.S. Patent 4,181,983 to Kulkarni and U.S. Pat. 4,186,448 to Brekke represent advances in the field of highly porous, biodegradable hydrophobic devices. Both patents show an improvement over U.S. Pat. 3,902,497 to Casey by preventing the encapsulation and isolation of the devices' interstices from a blood clot. Kulkarni and Brekke utilize a surfactant as part of the finished device in order to create a specific physical characteristic for the device; the ability to absorb fluid blood. Kulkarni and Brekke both teach that the surfactant is held in the structural filaments of the polymer and Kulkarni specifies that the surfactant must remain in the polymer in a sufficient amount to impart hydrophilicity to the device.
Stroetmann (U.S. Pat. No. 4,442,655) creates an aqueous mixture of fibrinogen (a hydrophilic material) and a biologically active substance which is then frozen and lyophilized to create a foam. This method results in the active agent being incorporated within the fibrinogen fibers and not on the surface.
Urist (U.S. Pat. No. 4,563,489) dissolved polylactic acid in a solvent forming a polymer solution. The solution was admixed with BMP and the solvent removed to create a composite which was formed into the desired shape. This method effectively traps the BMP in the polymer substance creating prolonged release kinetics which Urist states will result in bone formation over a considerable period of time. Urist (U.S. Pat. No. 4,596,574), in a separate patent, adds an aqueous solution of BMP to a hydrophilic biodegradable porous ceramic device (sintered), which is then dried to coat the internal surfaces of the device.
Caplan (U.S. Pat. No. 4,609,551) discloses a method wherein fibroblasts can be delivered to the site of a defect by immersing a biodegradable carrier in a solution of aquated BMP and fibroblasts so that the cells can attach or be trapped within the material to be implanted. All porous materials listed (fibrin clot, allograft) are hydrophilic by nature and would allow for easy integration of aqueous solutions within the matrix. Additionally, cell adhesion to a prosthesis was accomplished only on the external surface. Caplan (U.S. Pat. No. 4,620,327) further discloses a method of immobilizing BMP's on the surface of biodegradable materials using fibrin or gelatin. An aqueous solution of BMP and fibrin or gelatin is mixed and added to the biodegradable material after which it is dried trapping the BMP's.
In both Caplan patents, all porous material listed is hydrophilic, and the prosthetic devices are surface coated without mention of any internal hydrophobic porosity.
Vacanti (U.S. Pat. No. 5,041,138) discloses a method for making a cartilaginous structure utilizing a biodegradable polymer matrix. The method further comprises coating the polymer with a basement membrane (i.e. agar, gelatin, collagens, fibronectin, etc.) This coating was easily accomplished because the matrix used was an upbraided 17mm length piece of vicryl suture which formed a branching structure without an internal porosity.